Process for treating lameness with an osseous, articular or osteoarticular component in human or veterinary medicine, comprising the administration of a bisphosphonic acid derivative

ABSTRACT

The invention relates to a process for treating lameness with an osseous, articular or osteoarticular component, comprising the administration, to a human or to an animal not suffering from arthritis or from fractures, of an effective amount of a bisphosphonic acid derivative of formula:  
                 
in which: 
         R 1  represents a hydrogen atom, a halogen atom, a hydroxyl, an amino, a mono(C 1 -C 4 )alkylamino or a di(C 1 -C 4 )alkylamino;    R 2  represents a halogen atom, a linear alkyl comprising from 1 to 5 carbon atoms which is unsubstituted or substituted with a group chosen from a chlorine atom, a hydroxyl, an amino, a mono(C 1 -C 4 )alkylamino or a di(C 1 -C 4 )alkylamino; a (C 3 -C 7 )cycloalkylamino,    or R 2  represents a phenoxy, a phenyl, a thiol, a phenylthio, a chlorophenylthio, a pyridyl, a pyridylmethyl, a 1-pyridyl-1-hydroxymethyl, an imidazolylmethyl or a 4-thiomorpholinyl, of one of its pharmaceutically acceptable salts or of one of its hydrates.

The present invention relates to a process for treating lameness with anosseous, articular or osteoarticular component in human or veterinarymedicine, comprising the administration of a bisphosphonic acidderivative.

The term lameness is understood to refer to irregular gait caused by theperception of a pain by partially or fully bearing weight on one or morelimbs during the functioning of limbs prompted into motion.

Lameness can manifest itself clinically in an intermittent or continuousmanner for several days, several weeks or several months.

Lameness results more specifically from the appearance of painfullesions on the bone structure, the cartilages, the ligaments, thesynovial membrane or the connective tissue or from an anomaly of localvascularization. Thus, lameness is generally associated with one or moreof the following components:

an osseous component which is the result of a change in the bonearchitecture and/or in the bone growth cartilages at the site of thelameness, such as, for example, losses of bone substance, the formationof cysts, deformation of the bone or excessive thickening of the growthcartilages;

an articular component which is the result of a change in the structureof the articular cartilages, such as, for example, erosions of thecartilaginous surfaces and/or a change in the synovial membrane and/or achange in the articular ligaments;

a muscular component which is the result of a change in muscledevelopment, such as, for example, a muscular atrophy; and

a vascular component which is the result of a change in localvascularization, such as, for example, a reduction in vascularization ofthe injured region.

The invention is directed towards providing a process for treatinglameness with an osseous component and/or with an articular componentwhich appear in a person or an animal not suffering from fractures orarthritis. Hereinbelow, lameness is referred to by the expressionlameness with an osseous, articular or osteoarticular component. Itshould be understood, however, that the osseous, articular orosteoarticular component can be present alone or combined with amuscular component and/or with a vascular component.

Lameness with an osseous, articular or osteoarticular component appearin particular during osteoarthrosis, osteochondrosis, navicular diseaseor enthesopathy of the bony insertions of the tendons, of the ligamentsor of the aponeurosis.

Among the factors which can bring about lameness with an osseous,articular or osteoarticular component, mention may be made of constantand/or intense mechanical stresses on the locomotor apparatus. In thecase of a person or animal unprepared for physical exercise, theintensity of the mechanical stress capable of bringing about lamenessmay be relatively low.

In contrast, in the case of a person or animal prepared for physicalexercise, lameness will appear when subjected to a mechanical stresswhose force or repetitive nature exceeds the resistance capacities ofthe limbs. Certain animal species are more particularly inclined todevelop lameness with an osseous, articular and/or osteoarticularcomponent. This is especially the case for equidae animals.

In point of fact, in horses, the locomotor apparatus is stressed morefrequently than it is in other animal species, either during sportingcompetitions or when the horse is used by people as a mount. In thisanimal species, lameness represents one of the main clinical conditionsrequiring veterinary consultation. Their clinical description is wellknown; a fairly exhaustive review on this subject is presented in thebook “Les boiteries du cheval” [Lameness in horses] edited by O. R.Adams (published by Maloine, 1990). Lameness with an osseous, articularor osteoarticular component are the most common; descriptions haveespecially been given in the art for navicular disease or horsepodotrochlear syndrome, bone spavin or osteoarthrosis of the distalstage of the tarsus in horses, horse osteochondrosis and enthesopathy ofthe bony insertions of the tendons, or the ligaments or of theaponeurosis in horses.

Thus, the invention relates to a process for treating lameness with anosseous, articular or osteoarticular component, comprising theadministration, to a person or to an animal (for example a horse) notsuffering from fractures or from arthritis, of a bisphosphonic acidderivative.

The bisphosphonic acid derivatives which can be used in the context ofthe invention have the general formula:

in which:

R₁ represents a hydrogen atom, a halogen atom, a hydroxyl, an amino, amono(C₁-C₄)alkylamino or a di(C₁-C₄)alkylamino;

R₂ represents a halogen atom, a linear alkyl comprising from 1 to 5carbon atoms which is unsubstituted or substituted with a group chosenfrom a chlorine atom, a hydroxyl, an amino, a mono(C₁-C₄)alkylamino, adi(C₁-C₄)alkylamino; a (C₃-C₇)cycloalkylamino,

or R₂ represents a phenoxy, a phenyl, a thiol, a phenylthio, achlorophenylthio, a pyridyl, a pyridyl-methyl, a1-pyridyl-1-hydroxymethyl, an imidazolylmethyl or a 4-thiomorpholinyl.

The salts of these compounds with pharmaceutically acceptable inorganicor organic acids or bases can also be used in the context of theinvention. Examples of salts with acids are hydrochloride, hydrobromide,sulphate, acetate, hydrogensulphate, dihydrogenphosphate,methanesulphonate, methylsulphate, maleate, fumarate, sulphonate,2-naphthalenesulphonate, glycolate, gluconate, citrate, isethionate,benzoate, salicylate, ascorbate, tartrate, succinate, lactate,glutarate, toluenesulphonate and ascorbate. As examples of salts withinorganic or organic bases, mention may be made of ammonium salts oralkali metal salts such as, for example, sodium salts.

The hydrates of these compounds can similarly be used according to theinvention.

These compounds are described in particular in EP 623,347.

Among these bisphosphonic acid derivatives, mention may be made inparticular of the following compounds:

1-hydroxyethylidenebisphosphonic acid, whose internationalnonproprietary name is etidronic acid, and its sodium salts;

2-pyrid-2-ylethylidenebisphosphonic acid, whose internationalnonproprietary name is piridronic acid, and its sodium salts;

dichloromethylenebisphosphonic acid, whose international nonproprietaryname is clodronic acid, and its sodium salts;

3-amino-1-hydroxypropylidenebisphosphonic acid, whose internationalnonproprietary name is pamidronic acid, and its sodium salts;

4-amino-1-hydroxybutylidenebisphosphonic acid, whose internationalnonproprietary name is alendronic acid, and its sodium salts;

6-amino-11-hydroxyhexylidenebisphosphonic acid and its salts;

phenoxymethylenebisphosphonic acid and its salts;

thiomorpholinomethylenebisphosphonic acid and its salts;

4-chlorophenylthiomethylenebisphosphonic acid, whose internationalnonproprietary name is tiludronic acid, and its pharmaceuticallyacceptable salts, in particular the disodium salt;

1-hydroxy-2-(3-pyridyl)ethylidenebisphosphonic acid, whose internationalnonproprietary name is risedronic acid, and its sodium salts;

1-hydroxy-2-(2-imidazolyl)ethyl-1,1-bisphosphonic acid and its salts;

(cycloheptylamino)methylenebisphosphonic acid and its salts;

2-hydroxyethylidene-2-(3-pyridyl)-1,1-bisphosphonic acid and its sodiumsalts.

According to the present invention, the administration of tiludronicacid and of its pharmaceutically acceptable salts, in particular thedisodium salt, or of its hydrates is particularly preferred.

Bisphosphonic acid derivatives are known to inhibit bone resorption andto decrease the activity of osteoclasts, as is found in particular inthe following articles:

“Diphosphonates inhibit hydroxyapatite dissolution in vitro and boneresorption in tissue culture and in vivo”, Fleisch H., Russell R.,Francis M., Science, 1969, 165, 1262-1264

“Two modes of action of bisphosphonates on osteoclastic resorption ofmineralized matrix”, Boonekamp P. M., Van Der Wee-Pals L. J. A., VanWijk-Lennep, Thesing C. W., Bijvoet O. L. M., Bone Miner., 1986, 1,27-39

“Dichloromethylene bisphosphonate (Cl₂MBP) inhibits bone resorptionthrough injury to osteoclasts that resorb CIMBP coated bone”, FlanaghanA. M., Chambers T. J., Bone Miner., 1989, 6, 33.

Many bisphosphonic acid derivatives are in development or are alreadymarketed in human medicine in the treatment of bone complaints. A reviewof the therapeutic uses of these derivatives is presented in the book“Bisphosphonate on bones” edited by Bijvoet O. L. M., Fleisch H. A.,Canfield R. E. and Russell R. G. G. (Elsevier Science BV, 1995). Themain uses concern the treatment of bone complaints such as Paget'sdisease or osteoporosis. The other uses usually described are directedtowards the treatment of malignant hypercalcaemia, bone tumours or bonemetastasis. It has also been possible to demonstrate theanti-inflammatory activity of certain bisphosphonic acid derivatives ina model of arthritis in rats, induced by injection of mycobacterium.

However, the authors are unaware of any studies demonstrating theanti-inflammatory activity of these bisphosphonic acid derivatives inpathologies other than arthritis or more generally in other species (andfor example in man). More recently, the value of certain bisphosphonicacid derivatives in improving the repair of fractures has beendescribed. Reference will be made in particular to EP 600,834 or U.S.Pat. No. 5,488,041.

In another field, the use of bisphosphonic acid derivatives is alsodescribed in the diagnosis of certain bone complaints by scintigraphy.An example of such a use is reported by Keegan K. G., Wilson D. A.,Lattimer C. L., Twardock A. R., Ellersieck M. R. (Am. J. Vet. Res.,1996, 57, 415-421) in the scintigraphic evaluation of ^(99m)Tc-methylenediphosphonate labelling of the navicular region in horses with lamenesslocalized on the foot. However no mention is made of the clinicalbenefit provided by binding the bisphosphonic acid derivative in thebones of the palmar region.

The medical treatments most usually prescribed for lameness are directedtowards pain relief; this is the case, for example, for treatments withnon-steroidal anti-inflammatory medicines. However, these treatments areunsatisfactory since they do not treat the injuries which are the causeof the inflammation. Their efficacy is moreover limited to the period ofadministration, since the beneficial effects of the anti-inflammatoriesdisappear as soon as treatment has ended. Rest is also often recommendedto allow the region of the locomotor apparatus, which is the cause oflameness, to return to a normal state. More specifically, in horses, theuse of orthopaedic shoes is recommended. Even more particularly, in thisanimal species, the use of compounds which modify vascularization in thenavicular region is recommended in the treatment of navicular disease;it is for these conditions that isoxsuprine, a vasodilator, isprescribed by Gabriel A., Caudron I., Serteyn D., Collin B. in “Syndromenaviculaire: anatomie, étiopathogénie, diagnostic, traitement”[Navicular syndrome: anatomy, aetiopathology, diagnosis and treatment],Ann. Med. Vet., 1994, 138, 309-330).

Surprisingly, it has been found that bisphosphonic acid derivatives areuseful in the treatment of lameness with an osseous, articular orosteoarticular component. It has been shown, entirely unexpectedly, thatthe use of these derivatives allows a significant and long-lastingimprovement in the clinical signs of lameness, or even curing oflameness, even beyond the treatment period, and without any increase inbone density being detectable by radiological examination.

Thus, the beneficial effects observed are not thought to be linked tothe bone resorption-inhibiting activity of the bisphosphonic acidderivatives.

Such medicines can be used in human medicine and in veterinary medicine.

They can be administered via various routes of administration, forexample parenterally, orally, rectally, intra-articularly, cutaneously,transcutaneously or transdermally.

The mode of administration of such medicines is determined depending onthe species treated, age, weight and the severity of the pathology.

The administration rhythm can consist of a single administration orrepeated administrations. In the case of repeated administrations, thetreatment can be administered continuously or intermittently. When acontinuous treatment is chosen, the preferred administration rhythm maybe from a single daily administration to 3 daily administrations over aperiod which can range from a few days to a few months. When anintermittent treatment is chosen, one of the following administrationrhythms may be adopted: an administration every 2 or 3 days or a weekly,bimonthly or monthly administration over periods which can range from afew weeks to a few months.

The concentration of the medicine, in terms of bisphosphonic acidderivative, depends on the activity and on the duration of action ofthis derivative, the mode of administration, the age, the weight, thesex, the importance of the desired effect, the intended species or, forcertain animal species, the race.

For liquid preparations for parenteral or oral use, the concentration ofthe medicine, in terms of bisphosphonic acid derivative, can be between0.001% and 90% as a weight/volume ratio. For preparations intended forthe oral route, it can be between 0.001 mg and 10 g per dosage unit.

The medicine can also be in the form of an implant.

The doses during each administration of the medicines prepared accordingto the present invention, expressed relative to the body weight, canrange between 0.001 mg/kg and 100 mg/kg.

For example, doses of from 0.01 mg/kg/week to 1 mg/kg/week of tiludronicacid or of one of its salts may be administered intravenously to horses.

For an oral administration, the pharmaceutical composition which can beused according to the invention may be in the form of a tablet, agelatin capsule, a powder, a granule, drops or any other form which canbe administered orally.

The composition which can be used according to the invention may alsocontain ingredients usually used in pharmacy for the preparation of oralforms. Thus, the said composition can contain a disintegration agent, aflow agent, a lubricant and any excipient of suitable mass.

Lactose, cellulose or starches can be used as mass excipient. Stearicacid, magnesium stearate, L-leucine or, for example, glyceryltribehenate can be used as lubricant. Sodium carboxymethylstarch,cross-linked sodium carboxymethylcellulose or, for example, crosslinkedpolyvinylpyrrolidone can be used as disintegration agent. Pure silica orcolloidal silicon dioxide can be used as flow agent.

The present invention also relates to rapidly dissolving oral forms andto effervescent oral forms obtained by adding an effervescent couple tothe composition according to the invention. Tartaric acid and sodiumbicarbonate or citric acid and sodium bicarbonate can be used aseffervescent couple.

The invention also relates to the use of rapidly dissolving tablets,effervescent tablets and tablets covered with a coating. A compositioncontaining sodium lauryl sulphate according to European patent EP336,851 is particularly suitable.

For rectal administration, use is made of suppositories which areprepared with binders that melt at rectal temperature, for example cocoabutter or polyethylene glycols.

The preparations for injection are prepared by mixing one or morebisphosphonic acid derivatives with a pH regulator, a buffer agent, asuspension agent, a solubilization agent, a stabilizer, a tonicity agentand/or a preserving agent, and by converting the mixture into anintravenous, subcutaneous or intramuscular injection, according to astandard process. Where appropriate, the preparations for injection canbe lyophilized according to a standard process.

Examples of suspension agents include methylcellulose, polysorbate-80,hydroxyethylcellulose, acacia, powdered gum tragacanth, sodiumcarboxymethylcellulose and polyethoxylated sorbitan monolaurate.

Examples of solubilzing agents include castor oil solidified withpolyoxyethylene, polysorbate-80, nicotinamide, polyethoxylated sorbitanmonolaurate, macrogol and the ethyl ester of castor oil fatty acid.

In addition, Examples of the stabilizer includes sodium sulphite, sodiummetasulphite and ether, while examples of the preserving agent includesmethyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, sorbic acid, phenol,cresol and chlorocresol.

An example of a tonicity agent is mannitol.

During the preparation of the solutions or suspensions for injection, itis desirable to take care to ensure that these are isotonic with theblood.

EXAMPLE 1

A clinical study was carried out to evaluate the effects of a treatmentwith disodium tiludronate on horses which develop lameness duringnavicular disease (also known as podotrochlear syndrome).

The study was carried out on 24 horses, the diagnosis of the naviculardisease causing lameness being based on the following criteria:

-   -   local signs in the palmar region: heat, swelling, pain    -   functional signs of limping graded on a scale from 0 (no sign of        limping) to 4 (trouble in bearing weight when at rest and/or in        motion and difficulty in moving around)    -   a functional test of locomotion after flexing the palmar region,        also assessed on a scale from 0 (locomotion not changed by        flexure) to 4 (start of suppression of bearing weight)    -   a radiological examination to assess radiological signs in the        palmar region qualitatively.

To be included, the animal had to show no signs or lesions of septicarthritis, or any fractures of the bones in the palmar region. Also, itneeded to have not received an injection or anti-inflammatory treatmentin the joints of the palmar region.

The wearing of an orthoraedic shoe was not contra-indicated since mostof the animals had been laming for several weeks and were alreadywearing a shoe of this type.

All the animals received, as a single treatment, disodium tiludronate inthe form of an injectable solution administered intravenously at a doseof 0.1 mg/kg, at a weekly administration rate for 6 to 10 weeks. Thefirst day of treatment corresponds to D0.

To assess the effects of the treatment, the animals were reviewed 1month after D0 (M1), 2 months after D0 (M2) and 6 months after D0 (M6).The effects of the treatment were assessed with regard to:

-   -   the local signs, the functional signs and the test of locomotion        after flexure as defined during inclusion of the animal into the        test    -   a radiological examination to assess the change in the        radiological signs    -   an assessment of the resumption of the animal's sporting        activity.

Taking all these criteria into account allows the horse to be placed inone of the following categories after the 3 control examinations at M1,M2 and M6:

-   -   “very favourable” category: absence of local signs, grade 0 for        the functional test and signs; the animal resumed activity        comparable to that in which it was engaged before limping    -   “favourable” category: the local signs are very much attenuated,        the functional signs have been improved by 1 or 2 degrees, the        horse is ready to resume physical activity comparable to that in        which it was engaged before limping    -   “average” category: persistence of local signs, functional signs        improved by 1 degree; persistence of a locomotor difficulty        preventing the animal from resuming normal physical activity        “mediocre” category: persistence of the local signs, no        improvement in the functional signs “poor” category: no        improvement in the local or functional signs, or even worsening        of the local signs and of the functional signs.

The table below summarizes the effects of the treatment (expressed as apercentage of animals present in each category): Examination ExaminationExamination Category at M1 at M2 at M6 Very favourable 8% 26% 18%Favourable 46%  43% 46% Average 38%  26% 27% Mediocre 4%  5%  9% Poor 4% 0%  0%

These results demonstrate the beneficial effects of administration ofthe bisphosphonic acid derivative, by revealing a change in kinetics oflameness. The benefit of the treatment is optimal 2 months afteradministration of the treatment is started. The treatment leads to acomplete recovery for a quarter of the animals at the end of itsadministration. The benefit of the treatment is maintained in anentirely satisfactory manner beyond the treatment period.

Radiological examination did not reveal any change in kinetics of thepathological radiological signs in the palmar region.

EXAMPLE 2

A clinical study was carried out in order to evaluate the effects of atreatment with disodium tiludronate on horses which develop lamenessduring bone spavin (which is osteoarthrosis of the distal stage of thetarsus).

The test procedure and the clinical monitoring of the animals were thesame as those described in Example 1, except that the local, functionaland radiological signs were assessed in the region of the hock.

5 horses were included in this test.

The results obtained were as follows (expressed as a percentage ofanimals present in each category): Examination Examination ExaminationCategory at M1 at M2 at M6 Very favourable 0% 40%  40% Favourable 40% 60%  20% Average 60%  0% 20% Mediocre 0% 0%  0% Poor 0% 0% 20%

The change in lameness induced by bone spavin is favourable to veryfavourable in most of the animals after treatment. The persistence ofthe beneficial effects is also very satisfactory.

EXAMPLE 3

A clinical study was carried out to evaluate the effects of a treatmentwith disodium tiludronate on horses which develop lameness associatedwith bone lesions in the form of sub-chondral cysts duringosteochondrosis.

The test procedure and the clinical monitoring of the animals were thesame as those described in Example 1, except that the local, functionaland radiological signs were evaluated in the joints affected byosteochondrosis.

5 horses were included in this test.

The results obtained were as follows (expressed as a percentage ofanimals present in each category): Examination Examination ExaminationCategory at M1 at M2 at M6 Very favourable 40% 20% 60%  Favourable  0%40% 0% Average 40% 20% 0% Mediocre  0%  0% 40%  Poor 20% 20% 0%

These results demonstrate the clinical benefit afforded byadministration of the bisphosphonic acid derivative on the treatment oflameness associated with bone lesions during osteochondrosis.

EXAMPLE 4

A clinical study was carried out to evaluate the effects of a treatmentwith disodium tiludronate on horses which develop lameness duringenthesopathy of the insertion of the tendons and the ligaments.

The test procedure and the clinical monitoring of the animals were thesame as those described in Example 1, except that the local, functionaland radiological signs were evaluated in the region of the tendon orligament insertions at the source of lameness.

6 horses were included in this test.

The results obtained were as follows (expressed as a percentage ofanimals present in each category): Examination Examination ExaminationCategory at M1 at M2 at M6 Very favourable  0% 0% 40% Favourable 50%67%  40% Average 33% 33%   0% Mediocre 17% 0% 20% Poor  0% 0%  0%

These results demonstrate the clinical benefit afforded byadministration of the bisphosphonic acid derivative on the treatment oflameness caused by insertion enthesopathies.

1-11. (canceled)
 12. Process for treating lameness that appears during osteoarthrosis comprising the administration, to a human or to an animal not suffering from arthritis or from fractures, of an effective amount of a bisphosphonic acid derivative selected from the group consisting of: 1-hydroxyethylidenebisphosphonic acid and its sodium salts; 2-pyrid-2-ylethylidenebisphosphonic acid and its sodium salts; phenoxymethylenebisphosphonic acid and its salts; thiomorpholinomethylenebisphosphonic acid and its salts; 4-chlorophenylthiomethylenebisphosphonic acid and its salts; 1-hydroxy-2-(3-pyridyl)ethylidenebisphosphonic acid and its sodium salts; 1-hydroxy-2-(2-imidazolyl)ethyl-1,1-bisphosphonic acid and its salts; and 2-hydroxyethylidene-2-(3-pyridyl)-1,1-bisphosphonic acid and its sodium salts.
 13. Process according to claim 12, for treating an animal belonging to the equidae family.
 14. Process according to claim 12, for treating a horse.
 15. Process according to claim 12, comprising the administration of 0.001 mg/kg to 100 mg/kg of body weight of the bisphosphonic acid derivative.
 16. Process according to claim 12, for treating limps in horses, comprising the intravenous administration of 0.01 mg/kg/week to 1 mg/kg/week of tiludronic acid or one of its pharmaceutically acceptable salts.
 17. Process according to claim 12, comprising the oral administration of the bisphosphonic acid derivative.
 18. Process according to claim 12, comprising the parenteral administration of the isphosphonic acid derivative.
 19. Process according to claim 12, comprising the administration of the bisphosphonic acid derivative in the form of an implant.
 20. Process according to claim 12, in which the bisphosphonic acid derivative is 4-chlorophenylthiomethylenebisphosphonic acid. 